-
JAMA Network Open Mar 2023Disulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Disulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma.
OBJECTIVE
To evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma.
DESIGN, SETTING, AND PARTICIPANTS
This was a multicenter, open-label, randomized phase II/III clinical trial with parallel group design. Patients were recruited at 7 study sites in Sweden and 2 sites in Norway between January 2017 and November 2020. Eligible patients were 18 years or older, had a first recurrence of glioblastoma, and indication for treatment with alkylating chemotherapy. Patients were followed up until death or a maximum of 24 months. The date of final follow-up was January 15, 2021. Data analysis was performed from February to September 2022.
INTERVENTIONS
Patients were randomized 1:1 to receive either standard-of-care (SOC) alkylating chemotherapy alone, or SOC with the addition of disulfiram (400 mg daily) and copper (2.5 mg daily).
MAIN OUTCOMES AND MEASURES
The primary end point was survival at 6 months. Secondary end points included overall survival, progression-free survival, adverse events, and patient-reported quality of life.
RESULTS
Among the 88 patients randomized to either SOC (n = 45) or SOC plus disulfiram and copper (n = 43), 63 (72%) were male; the mean (SD) age was 55.4 (11.5) years. There was no significant difference between the study groups (SOC vs SOC plus disulfiram and copper) in 6 months survival (62% [26 of 42] vs 44% [19 of 43]; P = .10). Median overall survival was 8.2 months (95% CI, 5.4-10.2 months) with SOC and 5.5 months (95% CI, 3.9-9.3 months) with SOC plus disulfiram and copper, and median progression-free survival was 2.6 months (95% CI, 2.4-4.6 months) vs 2.3 months (95% CI, 1.7-2.6 months), respectively. More patients in the SOC plus disulfiram and copper group had adverse events grade 3 or higher (34% [14 of 41] vs 11% [5 of 44]; P = .02) and serious adverse events (41% [17 of 41] vs 16% [7 of 44]; P = .02), and 10 patients (24%) discontinued disulfiram treatment because of adverse effects.
CONCLUSIONS AND RELEVANCE
This randomized clinical trial found that among patients with recurrent glioblastoma, the addition of disulfiram and copper to chemotherapy, compared with chemotherapy alone, resulted in significantly increased toxic effects, but no significant difference in survival. These findings suggest that disulfiram and copper is without benefit in patients with recurrent glioblastoma.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16.
Topics: Humans; Male; Middle Aged; Female; Glioblastoma; Copper; Disulfiram; Quality of Life; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37000452
DOI: 10.1001/jamanetworkopen.2023.4149 -
Handbook of Experimental Pharmacology 2018For more than 25 years, researchers have made advances in developing medications to treat alcohol use disorder (AUD), highlighted by the US Food and Drug... (Review)
Review
For more than 25 years, researchers have made advances in developing medications to treat alcohol use disorder (AUD), highlighted by the US Food and Drug Administration's (FDA's) approval of disulfiram, naltrexone (oral and long-acting), and acamprosate. These medications are also approved in Europe, where the European Medicines Agency (EMA) recently added a fourth medication, nalmefene, for AUD. Despite these advances, today's medications have a small effect size, showing efficacy for only a limited number of individuals with AUD. However, a host of new medications, which act on variety of pharmacologic targets, are in the pipeline and have been evaluated in numerous human studies. This article reviews the efficacy and safety of medications currently being tested in human trials and looks at ongoing efforts to identify candidate compounds in human studies. As mentioned in the National Institute on Alcohol Abuse and Alcoholism's Strategic Plan 2017-2021 ( https://www.niaaa.nih.gov/sites/default/files/StrategicPlan_NIAAA_optimized_2017-2020.pdf ), medications development remains a high priority. By developing more effective and safe medications, and identifying those patients who will benefit the most from these treatments, we can provide clinicians with the tools they need to treat this devastating disorder, providing relief for patients and their families and markedly improving public health and safety.
Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Disulfiram; Humans; Naltrexone
PubMed: 29294197
DOI: 10.1007/164_2017_79 -
Cancer Chemotherapy and Pharmacology Feb 2021Cancer is a major health issue worldwide and the global burden of cancer is expected to reduce the costs of treatment as well as prolong the survival time. One of the... (Review)
Review
Cancer is a major health issue worldwide and the global burden of cancer is expected to reduce the costs of treatment as well as prolong the survival time. One of the promising approaches is drug repurposing, because it reduces costs and shortens the production cycle of research and development. Disulfiram (DSF), which was originally approved as an anti-alcoholism drug, has been proven safe and shows the potential to target tumours. Its anti-tumour effect has been reported in many preclinical studies and recently on seven types of cancer in humans: non-small cell lung cancer (NSCLC), liver cancer, breast cancer, prostate cancer, pancreatic cancer, glioblastoma (GBM) and melanoma and has a successful breakthrough in the treatment of NSCLC and GBM. The mechanisms, particularly the intracellular signalling pathways, still remain to be completely elucidated. As shown in our previous study, DSF inhibits NF-kB signalling, proteasome activity, and aldehyde dehydrogenase (ALDH) activity. It induces endoplasmic reticulum (ER) stress and autophagy and has been used as an adjuvant therapy with irradiation or chemotherapy drugs. On the other hand, DSF not only kills the normal cancer cells but also has the ability to target cancer stem cells, which provides a new approach to prevent tumour recurrence and metastasis. Furthermore, other researchers have reported the ability of DSF to bind to nuclear protein localization protein 4 (NPL4), induce its immobilization and dysfunction, ultimately leading to cell death. Here, we provide an overview of DSF repurposing as a treatment in preclinical studies and clinical trials, and review studies describing the mechanisms underlying its anti-neoplastic effects.
Topics: Animals; Antineoplastic Agents; Disulfiram; Drug Repositioning; Humans; Neoplasms; Neoplastic Stem Cells
PubMed: 33426580
DOI: 10.1007/s00280-020-04216-8 -
International Journal of Antimicrobial... May 2022The objective of this systematic review was to retrieve and examine published studies related to in vitro and in vivo evaluation of disulfiram for the treatment of... (Review)
Review
The objective of this systematic review was to retrieve and examine published studies related to in vitro and in vivo evaluation of disulfiram for the treatment of bacterial infections. Five scientific databases (PubMed, Embase, Scopus, Web of Science, and Latin American and Caribbean Health Sciences Literature) were searched to retrieve the maximum literature regarding the study's aim. The search strategy retrieved a total of 870 studies, of which 31 were included and 19 approached disulfiram as the primary aim and 12 included it as a secondary finding from other investigational objectives. The evidence pointed out five main aspects of pre-clinical testing regarding disulfiram antibacterial activity, namely spectrum of antimicrobial action, drug combinations, intracellular studies, animal studies and bacterial targets. Findings to emerge from this study are the observed potential of disulfiram as a non-antibiotic drug being proposed as a potential drug to contribute to the treatment of bacterial diseases usually with few treatment alternatives in the context of drug resistance. We evaluated the potency and selectivity of disulfiram, which indeed until now shows potential to be explored for use as an adjunctive chemical to antimicrobial ones. Even with the level of evidence being reserved, the potential of combining disulfiram with other drugs, already used or new to be used for the treatment of mycobacterial diseases, as well as its likely immunomodulatory effect, deserve to be further investigated. Furthermore, the copper-dependent mode of action in Gram-positive bacteria is an alternative to be explored in drug design or repurposing of chemicals.
Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Infections; Disulfiram; Gram-Positive Bacteria
PubMed: 35367599
DOI: 10.1016/j.ijantimicag.2022.106578 -
Cellular & Molecular Immunology Mar 2024STING (also known as MITA) is an adaptor protein that mediates cytoplasmic DNA-triggered signaling, and aberrant activation of STING/MITA by cytosolic self-DNA or...
STING (also known as MITA) is an adaptor protein that mediates cytoplasmic DNA-triggered signaling, and aberrant activation of STING/MITA by cytosolic self-DNA or gain-of-function mutations causes severe inflammation. Here, we show that STING-mediated inflammation and autoimmunity are promoted by RNF115 and alleviated by the RNF115 inhibitor disulfiram (DSF). Knockout of RNF115 or treatment with DSF significantly inhibit systemic inflammation and autoimmune lethality and restore immune cell development in Trex1 mice and STING bone marrow chimeric mice. In addition, knockdown or pharmacological inhibition of RNF115 substantially downregulate the expression of IFN-α, IFN-γ and proinflammatory cytokines in PBMCs from patients with systemic lupus erythematosus (SLE) who exhibit high concentrations of dsDNA in peripheral blood. Mechanistically, knockout or inhibition of RNF115 impair the oligomerization and Golgi localization of STING in various types of cells transfected with cGAMP and in organs and cells from Trex1 mice. Interestingly, knockout of RNF115 inhibits the activation and Golgi localization of STING as well as the expression of proinflammatory cytokines in myeloid cells but not in endothelial cells or fibroblasts. Taken together, these findings highlight the RNF115-mediated cell type-specific regulation of STING and STING and provide potential targeted intervention strategies for STING-related autoimmune diseases.
Topics: Humans; Mice; Animals; Autoimmunity; Disulfiram; Endothelial Cells; Mice, Knockout; Inflammation; Autoimmune Diseases; Cytokines; DNA; Ubiquitin-Protein Ligases
PubMed: 38267694
DOI: 10.1038/s41423-024-01131-3 -
Therapeutische Umschau. Revue... Oct 2014Alcohol addiction is a common problem in daily life as well as in medicine. Apart from inpatient therapy programs, ambulatory withdrawal is a relatively new option,... (Review)
Review
Alcohol addiction is a common problem in daily life as well as in medicine. Apart from inpatient therapy programs, ambulatory withdrawal is a relatively new option, which may be done safely, efficient and cost-effective close to the domicile an without stigmatisation of the patient.
Topics: Alcoholism; Ambulatory Care; Cost Savings; Cross-Sectional Studies; Disulfiram; Health Care Costs; Humans; Psychotherapy, Group; Self-Help Groups; Substance Abuse Treatment Centers; Switzerland; Treatment Outcome
PubMed: 25257113
DOI: 10.1024/0040-5930/a000558 -
Current Pharmaceutical Biotechnology 2017Alcohol addiction or alcoholism is the most severe form of problem drinking. A variety of treatment methods for alcoholism are currently available that combine... (Review)
Review
Alcohol addiction or alcoholism is the most severe form of problem drinking. A variety of treatment methods for alcoholism are currently available that combine medications, behavioral treatment and peer support. The drugs that are currently approved by the U.S. Food and Drug Administration (FDA) for treatment of alcohol dependence are disulfiram, naltrexone and acamprosate. For many patients, however, these treatments are not effective. Evidence from a number of studies suggests that various factors, both psychosocial and economic, as well as genetic variation, are significant contributors to interindividual variation both of clinical presentation of alcohol problems and response to a given treatment. The aim of the present review is to summarize and discuss different aspects of personalized medicine of alcohol addiction. We focus on pharmacogenomics and beyond, to include the genetics and epigenetics of alcohol addiction as well as other psychosocial and even economic factors that may affect response to alcohol addiction pharmacotherapy. It is anticipated that, within the next 5-10 years, personalized medicine of alcohol addiction will be a reality and it will help reduce the burden of alcoholism from society and increase the well-being and productivity of individuals addicted to alcohol.
Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Disulfiram; Humans; Naltrexone; Pharmacogenetics; Polymorphism, Genetic; Precision Medicine; Taurine
PubMed: 28240173
DOI: 10.2174/1389201018666170224105025 -
Pharmacogenetics and Genomics Dec 2023
Topics: Humans; Disulfiram
PubMed: 37728645
DOI: 10.1097/FPC.0000000000000509 -
Journal of Psychosocial Nursing and... Dec 2021Alcohol use disorder (AUD) is a serious, prevalent disorder that affects millions of people. There are numerous evidence-based treatments and strategies to treat AUD,... (Review)
Review
Alcohol use disorder (AUD) is a serious, prevalent disorder that affects millions of people. There are numerous evidence-based treatments and strategies to treat AUD, but they are under-utilized for a variety of reasons, including provider stigma, lack of knowledge, lack of professional support, shortage of willing providers, and patient barriers. Disulfiram, naltrexone, and acamprosate are approved but underused medications for the treatment of AUD. Nonpharmacological strategies and treatments include the use of motivational interviewing when talking to patients about their alcohol use, peer support or mutual help groups, and individualized therapy. Nurses are in a prime position to educate themselves and patients on evidence-based treatments for AUD and to help patients access those treatments. [(12), 7-11.].
Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Disulfiram; Humans; Naltrexone
PubMed: 34846245
DOI: 10.3928/02793695-20211110-01 -
Frontiers in Bioscience (Landmark... Aug 2023The complex formed by disulfiram (DSF) and copper (Cu) is safe and effective for the prevention and treatment of triple-negative breast cancer (TNBC). Although previous...
BACKGROUND
The complex formed by disulfiram (DSF) and copper (Cu) is safe and effective for the prevention and treatment of triple-negative breast cancer (TNBC). Although previous studies have shown that DSF/Cu induces ferroptosis, the mechanism remains unclear.
METHODS
The mitochondrial morphology of TNBC treated with DSF/Cu was observed by transmission microscopy, and intracellular levels of iron, lipid reactive oxygen species (ROS), malondialdehyde, and glutathione were evaluated to detect the presence of ferroptosis. Target genes for the DSF/Cu-activated ferroptosis signaling pathway were examined by transcriptome sequencing analysis. Expression of the target gene, , was detected by qRT-PCR, immunofluorescence and western blot.
RESULTS
The mitochondria of TNBC cells were significantly atrophied following treatment with DSF/Cu for 24 h. Addition of DSF/Cu supplement resulted in significant up-regulation of intracellular iron, lipid ROS and malondialdehyde levels, and significant down-regulation of glutathione levels, all of which are important markers of ferroptosis. Transcriptome analysis confirmed that DSF/Cu activated the ferroptosis signaling pathway and up-regulated several ferroptosis target genes associated with redox regulation, especially heme oxygenase-1 (HMOX-1). Inhibition of ferroptosis by addition of the ROS scavenger N-acetyl-L-cysteine (NAC) significantly increased the viability of DSF/Cu-treated TNBC cells.
CONCLUSIONS
These results show that DSF/Cu increases lipid peroxidation and causes a sharp increase in HMOX1 activity, thereby inducing TNBC cell death through ferroptosis. DSF/Cu is a promising therapeutic drug for TNBC and could lead to ferroptosis-mediated therapeutic strategies for human cancer.
Topics: Humans; Triple Negative Breast Neoplasms; Copper; Disulfiram; Ferroptosis; Reactive Oxygen Species; Cell Line; Glutathione; Lipids
PubMed: 37664913
DOI: 10.31083/j.fbl2808186